3 years ago

A Single TCF Transcription Factor, Regardless of Its Activation Capacity, Is Sufficient for Effective Trilineage Differentiation of ESCs

A Single TCF Transcription Factor, Regardless of Its Activation Capacity, Is Sufficient for Effective Trilineage Differentiation of ESCs
Steven Moreira, Bradley W. Doble, Alexandre Blais, Jiayi Cao, Solen Abdulla, Victor Gordon, Enio Polena, Anna Dvorkin-Gheva, Geoffrey A. Wood, Sujeivan Mahendram

Summary

Co-expression and cross-regulation of the four TCF/LEFs render their redundant and unique functions ambiguous. Here, we describe quadruple-knockout (QKO) mouse ESCs lacking all full-length TCF/LEFs and cell lines rescued with TCF7 or TCF7L1. QKO cells self-renew, despite gene expression patterns that differ significantly from WT, and display delayed, neurectoderm-biased, embryoid body (EB) differentiation. QKO EBs have no contracting cardiomyocytes and differentiate poorly into mesendoderm but readily generate neuronal cells. QKO cells and TCF7L1-rescued cells cannot efficiently activate TCF reporters, whereas TCF7-rescued cells exhibit significant reporter responsiveness. Surprisingly, despite dramatically different transactivation capacities, re-expression of TCF7L1 or TCF7 in QKO cells restores their tri-lineage differentiation ability, with similar lineage marker expression patterns and beating cardiomyocyte frequencies observed in EBs. Both factors also similarly affect the transcriptome of QKO cells. Our data reveal that a single TCF, regardless of its activation capacity, is sufficient for effective trilineage differentiation of ESCs.

Publisher URL: http://www.cell.com/cell-reports/fulltext/S2211-1247(17)31150-6

DOI: 10.1016/j.celrep.2017.08.043

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